U.S. Food and Drug Administration Approval: Cabozantinib for the Treatment of Advanced Renal Cell Carcinoma Harpreet Singh, Michael Brave, Julia A

Published OnlineFirst October 28, 2016; DOI: 10.1158/1078-0432.CCR-16-1073

CCR Drug Updates Clinical Cancer Research U.S. Food and Drug Administration Approval: Cabozantinib for the Treatment of Advanced Renal Cell Carcinoma Harpreet Singh, Michael Brave, Julia A. Beaver, Joyce Cheng, Shenghui Tang, Eias Zahalka, Todd R. Palmby, Rajesh Venugopal, Pengfei Song, Qi Liu, Chao Liu, Jingyu Yu, Xiao Hong Chen, Xing Wang,Yaning Wang, Paul G. Kluetz, Selena R. Daniels, Elektra J. Papadopoulos, Rajeshwari Sridhara, Amy E. McKee, Amna Ibrahim, Geoffrey Kim, and Richard Pazdur

Abstract

On April 25, 2016, the FDA approved cabozantinib median PFS of 7.4 and 3.8 months in the cabozantinib and (Cabometyx; Exelixis, Inc.) for the treatment of advanced renal everolimus arms, respectively [hazard ratio (HR), 0.58; 95% cell carcinoma (RCC) in patients who have received prior confidence interval (CI), 0.45–0.74; P < 0.0001]. At a second antiangiogenic therapy. The approval was based on data from interim analysis, a statistically significant improvement in one randomized, open-label, multicenter study in which overall survival (OS) in the intent-to-treat population was also patients with RCC who had received prior antiangiogenic demonstrated, with a median OS of 21.4 and 16.5 months in therapy were treated with either cabozantinib 60 mg orally the cabozantinib and everolimus arms, respectively (HR, 0.66; once daily (n ¼ 330) or everolimus 10 mg orally once daily (n ¼ 95% CI, 0.53–0.83; P ¼ 0.0003). The most common (greater 328). The major efficacy outcome measure was progression-free than or equal to 25%) adverse reactions included diarrhea, survival (PFS) as assessed by a blinded independent radiology fatigue, nausea, decreased appetite, palmar–plantar erythrody- review committee in the first 375 randomized patients. A sesthesia syndrome, hypertension, vomiting, weight loss, and statistically significant improvement in PFS was seen, with a constipation. Clin Cancer Res; 23(2); 330–5. 2016 AACR.

Introduction Lenvatinib, a multiple TKI, was approved in combination with everolimus in May 2016 based on an improved PFS of 14.6 In 2015, it is estimated that there will be 61,560 new cases and months compared with 5.5 months with everolimus alone (5). 14,080 deaths from renal cell carcinoma (RCC) in the United Cabozantinib was previously approved in 2012 with a capsule States (1). Advanced RCC is most commonly treated with anti- formulation (Cometriq; Exelixis, Inc.) for the treatment of met- angiogenic therapy in the first-line setting, and, after initial astatic medullary thyroid cancer (MTC). During the development progression, the median progression-free survival (PFS) and of cabozantinib for RCC, the application was granted Break- overall survival (OS) can be as little as 5 and 20 months, respec- through Therapy designation, Fast Track, and Priority Review tively. Although there is an unmet medical need to improve (6). The FDA approval summary of the marketing application clinical outcomes in advanced RCC, new treatment paradigms for cabozantinib tablets is provided below. are emerging. There are currently four approved therapies for advanced RCC in the second-line setting: everolimus, axitinib, nivolumab, and lenvatinib in combination with everolimus. Chemistry Everolimus is an mTOR inhibitor that demonstrated a median The(S)-malate salt of cabozantinib is described chemically PFS improvement over placebo of 4.9 versus 1.9 months (2). as N-(4-(6,7-dimethoxyquinolin-4-yloxy)phenyl)-N'-(4-fluoro- Axitinib, a tyrosine kinase inhibitor (TKI), demonstrated a medi- phenyl) cyclopropane-1,1-dicarboxamide, (2S)-hydroxybutane- an PFS improvement over sorafenib of 6.7 versus 4.7 months (3). dioate. The commercial cabozantinib drug product tablet Nivolumab, an immunotherapy, was approved in 2015 with a formulation (Cabometyx; Exelixis, Inc.) is marketed in three median OS benefit over everolimus of 25 versus 19.6 months (4). strengths (20, 40, and 60 mg).

Nonclinical Pharmacology and Toxicology U.S. Food and Drug Administration, White Oak, Maryland. Cabozantinib is an inhibitor of receptor tyrosine kinases, Note: This is a U.S. Government work. There are no restrictions on its use. including MET; VEGFR-1, -2, and -3; AXL; RET; ROS1; TYRO3; Corresponding Author: Harpreet Singh, U.S. Food and Drug Administration, MER; KIT; TRKB; FLT-3; and TIE-2. These receptor tyrosine kinases Center for Drug Evaluation and Research (CDER), 10903 New Hampshire are involved in both normal cellular function and pathologic Avenue, WO 22 Room 2137, Silver Spring, MD 20993. Phone: 240-402-3561; processes, such as oncogenesis, metastasis, tumor angiogenesis, Fax: 301-796-9845; E-mail: [email protected] drug resistance, and maintenance of the tumor microenviron- doi: 10.1158/1078-0432.CCR-16-1073 ment (7). There is a rationale in targeting both AXL and MET when 2016 American Association for Cancer Research. considering acquired resistance to VEGR inhibitors in RCC. In

330 Clin Cancer Res; 23(2) January 15, 2017

FDA Approval Summary for Cabozantinib for RCC

preclinical studies, the inhibition of AXL and MET suggested that independent radiology review committee (IRC) according to treatment with cabozantinib may overcome resistance to pro- RECIST v1.1 among the first 375 patients randomized [primary longed VEGF therapy (8). endpoint intent-to-treat population (PITT)]. At the clinical trial Supporting nonclinical pharmacology and toxicology data design stage, it was determined that a sample size of 375 patients submitted for this New Drug Application (NDA) were previously with 259 PFS events observed would have 90% power to detect a reviewed during the metastatic MTC cabozantinib review, and hazard ratio (HR) of 0.667 at a two-sided 5% significance level updated carcinogenicity data were submitted in fulfilment of a using a stratified log-rank test. PFS was defined as the time from postmarketing requirement (PMR) under the MTC application randomization to the earlier of the following events: documented (9). Cabozantinib was not carcinogenic in a 26-week carcinoge- progressive disease (PD) per RECIST v1.1 or death due to any nicity study in rasH2 transgenic mice. cause. Other efficacy endpoints included OS defined as the time from randomization until death due to any cause and objective Clinical Pharmacology response rate (ORR) per RECIST v1.1 as assessed by the IRC. It was determined that a sample size of 650 patients with 408 Following oral administration of cabozantinib tablet formu- deaths observed would have 80% power to detect an HR of lation, median time to peak cabozantinib plasma concentration 0.75 at a two-sided 4% level of significance using a stratified (T ) ranged from 2 to 3 hours after dosing. A 19% increase in the max log-rank test. Interim analyses were planned to be conducted at C of the tablet formation compared with the capsule formu- max the time of PFS analysis and when 135 events were observed. As lation was observed following a single 140 mg dose. A less the number of events necessary to evaluate the PFS endpoint than 10% difference in the AUC was observed between cabozan- could have occurred before the study was fully accrued and in tinib tablet and capsule formulations. The food effect on the order not to bias the results toward subjects whose disease pharmacokinetics of cabozantinib with the tablet formulation progressed early, the PFS analysis was determined from only the is unknown. Cabozantinib, therefore, is recommended to be first 375 patients randomized. The primary endpoint PFS and administered on an empty stomach to minimize the risk of any secondary endpoint OS analyses by the applicant were stratified clinically meaningful effect of food intake on plasma exposure. by the number of prior VEGFR-targeting TKI therapies (1 vs. 2 or The oral volume of distribution (V /F) of cabozantinib is approx- z more) and Memorial Sloan Kettering Cancer Center (MSKCC, imately 319 L. Cabozantinib is highly protein bound in human New York, NY) prognostic criteria for previously treated patients plasma (99.7%). The predicted terminal half-life is approxi- with RCC (0 vs. 1 vs. 2 or 3) as collected on the electronic case mately 99 hours, and the clearance (CL/F) at a steady state is report forms. To follow the ITT principle, the review team con- estimated to be 2.2 L/hour. Increased exposure to cabozantinib ducted additional analyses based on interactive voice response has been observed in patients with mild-to-moderate hepatic (IVRS). impairment; thus, the dose of cabozantinib should be reduced Patient-reported outcomes (PRO) were collected for explor- in these patients. Although dosage adjustment is not required in atory purposes every 4 weeks through W25D1, followed by every patients with mild or moderate renal impairment, there is no 8 weeks until the date of the last tumor imaging assessment, and experience with cabozantinib in patients with severe renal were analyzed in the ITT population using two-sided statistical impairment. tests without adjustment for multiplicity. The PRO instruments Cross-study pharmacokinetics analysis indicated similar used included the 19-item Functional Assessment of Cancer steady-state exposures (C ) at different doses across patient trough,ss Therapy-Kidney Cancer Symptom Index (FKSI-19) and the populations with MTC (140 mg capsule), RCC (60 mg tablet), EuroQol five-dimensions questionnaire (EQ-5D-5L). and castration-resistant prostate cancer (60 mg tablet). In addition, the apparent oral clearance estimated by population pharmacokinetics model was 4.4 L/hour in MTC and 2.2 L/hour in Demographics, Disease Characteristics, RCC. This result was unexpected, as Cmax and AUC of the tablet and Prior Treatment formulation (Cabometyx) and the capsule formulation (Come- All patients had advanced RCC with a clear cell component by triq) were similar following a single 140-mg dose. Therefore, a histology or cytology. The majority of the patients were male postmarketing commitment was requested to evaluate the poten- (75%), with a median age of 62 years. Sixty-nine percent received tial impact of patient population, formulations, and doses on the only one prior antiangiogenic therapy. Patient allocation by pharmacokinetics of cabozantinib in an integrated population MSKCC risk groups included 46% of patients in the favorable pharmacokinetics model with the pooled pharmacokinetics data group (no risk factors), 42% in the intermediate group (one risk from different patient populations and healthy patients. factor), and 13% in the poor group (two or three risk factors). Fifty-four percent of patients had three or more organs with Clinical Trials metastatic disease, including lung (63%), lymph nodes (62%), The approval of cabozantinib was based on a randomized, liver (29%), and bone (22%). Approximately 5% of patients had – – open-label, multicenter trial (trial XL184-30/METEOR) compar- prior treatment with PD-L1 or PD-1 blocking antibodies. In ing cabozantinib with everolimus in 658 patients with advanced general, the treatment arms were balanced with respect to age, RCC who had received at least one prior antiangiogenic therapy gender, race, ethnicity, enrollment region, number of prior ther- (10, 11). Patients were randomized to receive cabozantinib orally apies, MSKCC risk factors, and prior cancer therapies. at 60 mg daily or everolimus orally at 10 mg daily. Treatment was fi continued until disease progression or unacceptable toxicity. Ef cacy Results Patients in either arm who experienced disease progression were PFS results at the time of the data cutoff are shown in Table 1 able to continue treatment at the discretion of the investigator. and Fig. 1. For the PITT population, the minimum time The primary efficacy outcome measure was PFS as assessed by an of follow-up was 10.7 months. A statistically significant

www.aacrjournals.org Clin Cancer Res; 23(2) January 15, 2017 331

Singh et al.

Table 1. PFS (first 375 randomized) zantinib and 43% of patients receiving everolimus. The most Endpoint Cabozantinib Everolimus common serious AEs in the cabozantinib-treated group (great- n ¼ 187 n ¼ 188 er than or equal to 2%) were abdominal pain, pleural effusion, Number of events (%) 121 (65%) 126 (67%) diarrhea, nausea, and anemia. Fifteen deaths were reported Median PFS (95% CI), months 7.4 (5.6–9.1) 3.8 (3.7–5.4) HR (95% CI), Pa 0.58 (0.45–0.74), P < 0.0001 within 30 days of the last cabozantinib dose. Eight of the deaths were attributed to PD, five deaths were due to general aStratified log-rank test with prior VEGFR-targeting TKI therapy (1 vs. 2 or more) and MSKCC prognostic criteria for previously treated patients with RCC (0 vs. 1 vs. physical health deterioration, pneumonia, postprocedural 2 or 3) as stratification factors (per IVRS data). hemorrhage, cardiac failure, and urosepsis, and two deaths were due to unexplained reasons. Sixty percent of patients treated with cabozantinib had at least one dose reduction while improvement in PFS was observed in patients receiving cabo- on study. Ten percent of patients in the cabozantinib group zantinib compared with everolimus, with a 3.6-month differ- required treatment discontinuation, and 70% required dose ence in median PFS (7.4 months vs. 3.8 months, respectively). modification, including dose interruption or dose reduction. ORR showed a statistically significant improvement in the The most frequent AEs leading to dose reduction of cabozanti- cabozantinib arm compared with the everolimus arm, with a nib were diarrhea (16%), palmar–plantar erythrodysesthesia 17% ORR [95% confidence interval (CI), 13–22] and 3% ORR syndrome (11%), fatigue (10%), and hypertension (7.6%). (95% CI, 2–6), respectively. The safety profile of cabozantinib in RCC appeared similar to At the time of the primary PFS analysis, the OS data were not the previously characterized profile of the capsule formulation of mature, and no statistically significant improvement was seen at cabozantinib in the MTC population. Patients treated with the an interim analysis. However, a second interim analysis was 60-mg tablet formulation used in the RCC study experienced conducted in the ITT population with at least 12 months of fewer events, such as gastrointestinal perforations and fistulas, follow-up, and a statistically significant difference in OS was compared with those treated with the 140-mg capsule formula- observed, with results shown in Table 2 and Fig. 2. tion in the MTC trial. However, the rates of other AEs, such as diarrhea, hypertension, and palmar–plantar erythrodysesthesia syndrome, were similar across tumor types. Safety Results Given the frequency of dose reductions, further simulations Safety was evaluated in 331 patients treated with cabozanti- and modeling were undertaken. In an FDA exposure–PFS rela- nib. The most common (greater than or equal to 25%) adverse tionship analysis, the relationship was explored by Cox regression E reactions included diarrhea, fatigue, nausea, vomiting, consti- model, where the drug exposure effect on hazard was an max pation, decreased appetite, hypertension, palmar–plantar ery- function of the pharmacokinetic model–predicted cabozantinib throdysesthesia syndrome, and weight loss. Serious adverse exposure. The model indicated that exposure under lower dose events (AE) were reported in 40% of patients receiving cabo- levels (e.g., 40 or 20 mg) may result in an inferior PFS compared

1.0 Cabozantinib Everolimus 0.8

0.6

0.4

0.2 Figure 1. PFS per IRC (PITT population).

0.0 Probability of progression-free survival 0 3 6 9 12 15 18 Progression-free survival (months) Number at risk Cabozantinib 187 152 92 68 20 62 Everolimus 188 99 46 29 10 2

332 Clin Cancer Res; 23(2) January 15, 2017 Clinical Cancer Research

FDA Approval Summary for Cabozantinib for RCC

Table 2. OS and ORR (ITT) Discussion Endpoint Cabozantinib Everolimus n ¼ 330 n ¼ 328 The landscape of metastatic RCC is evolving with newer ther- Number of events (%) 140 (42%) 180 (55%) apies, and it is unclear how clinical practice will be impacted. Until Median OS (95% CI), months 21.4 (18.7–NE) 16.5 (14.7–18.8) recently, most of the available therapies for patients with a HR (95% CI), P 0.66 (0.53–0.83), P ¼ 0.0003 advanced RCC in the second-line setting were approved on the fi – – Con rmed ORR (partial 17% (13% 22%) 3% (2% 6%) basis of improvements in PFS. However, with the approvals of responses only; 95% CI) Pb P < 0.0001 nivolumab, lenvatinib in combination with everolimus, and cabozantinib, the landscape for FDA-approved available thera- aStratified log-rank test with prior VEGFR-targeting TKI therapy (1 vs. 2 or more) and MSKCC prognostic criteria for previously treated patients with RCC (0 vs. 1 pies in the second-line setting has shifted to include agents with vs. 2 or 3) as stratification factors (per IVRS data). OS benefit and varying toxicity profiles (Table 3). Clinical practice bc2 test. will dictate which second-line regimen for patients with metastatic RCC is preferred. For the purposes of the cabozantinib approval, despite other available therapies in this setting, ever- with 60 mg daily. Taking the cabozantinib concentration of olimus, as an approved drug for advanced RCC, was considered an 1,125 ng/mL (median concentration at 60 mg every-day dose) appropriate active comparator. as the reference, the HR would be 1.1 and 1.39 if the exposure was A review issue revolved around appropriateness of dose reduced to 67% and 33% of the reference concentration, respec- selectiongiventhehighpercentageofdosereductions. tively. Modeling and simulations showed a predicted median Although there was a high percentage of dose reductions in percentage change of tumor size from baseline of 4.5%, 9.1%, the cabozantinib arm, there was a lower percentage of dose and 11.9% with 20-, 40-, and 60-mg starting dose, respectively. discontinuation compared with everolimus, suggesting that These reductions in tumor size correspond to a predicted ORR most adverse reactions were successfully managed with dose (based on target lesion) of 8.7%, 15.6%, and 19.1% with the 20-, interruptions and supportive measures. A comprehensive anal- 40-, and 60-mg dose, respectively. ysis of the adverse reactions causing dose reduction did not identify a serious risk, a signal of a serious risk, or an unexpected serious risk related to the use of the drug, and, therefore, PRO Results criteria for a safety PMR were not met (12). In addition, Exploratory PRO results were limited by the open-label clinical exposure–response and pharmacometric modeling indicated trial design and moderate levels of missing data. A repeated- that lower starting doses could possibly compromise activity measures analysis of the change from baseline showed no clear, of the drug with decreased response rates. Therefore, the review clinically meaningful differences for the EQ-5D and FKSI-total team concluded that the dose selection of 60 mg daily was score and three of the four subscales. The treatment side effects adequate based on exposure–response analyses and a safety subscale of the FKSI-19 was numerically worse for patients on the profile that is acceptable for the patient population. In addi- cabozantinib arm, with the largest effect seen with numerically tion, the cabozantinib label specifies dose-reduction instruc- worse diarrhea. tions for the RCC population and describes the frequency of

1.0 Cabozantinib Everolimus 0.8

0.6

0.4

Figure 2. 0.2 Probability of OS OS (second interim analysis; ITT population). 0.0 0 3 6 9 12 15 18 21 24 27 30

Number at risk OS (months) Cabozantinib 330 318 296 264 239 178 105 41 6 3 Everolimus 328 307 262 229 202 141 82 32 8 1

www.aacrjournals.org Clin Cancer Res; 23(2) January 15, 2017 333

Singh et al.

Table 3. FDA-approved therapies indicated for second-line treatment of patients with advanced RCC Approval FDA-approved drug year Trial design/population Endpoint(s) Clinical benefit/effect Afinitor (everolimus; Novartis) 2009 Multicenter, randomized, PFS (by central Everolimus vs. placebo double blinded, two arm review) Prior sorafenib or sunitinib PFS: HR, 0.33 (95% CI, 0.25–0.43); median 4.9 vs. 1.9 m Inlyta (axitinib; Pfizer) 2012 Multicenter, randomized, PFS (by central Axitinib vs. sorafenib open label, two arm review) Prior antiangiogenic or PFS: HR, 0.67 (95% CI, 0.54–0.81); median 6.7 vs. 4.7 m cytokine therapy Opdivo (nivolumab; 2015 Prior antiangiogenic therapy OS Nivolumab vs. everolimus Bristol-Myers Squibb) OS: HR, 0.73 (95% CI, 0.60–0.89); median 25.0 vs. 19.6 m PFS: HR, 0.88 (95% CI, 0.75–1.03); median 4.6 vs. 4.4 m Cabometyx (cabozantinib; 2016 Prior antiangiogenic therapy PFS Cabozantinib vs. everolimus Exelixis, Inc.) PFS: HR, 0.58 (95% CI, 0.45–0.74); median 7.4 vs. 3.8 m OS: HR, 0.66 (95% CI, 0.53–0.83); median 21.4 vs. 16.5 m Lenvima (lenvatinib; Eisai) 2016 Prior antiangiogenic therapy PFS Lenvatinib plus everolimus vs. lenvatinib vs. everolimus in combination with PFS: HR, 0.37 (95% CI, 0.22–0.62); median 14.6 vs. 5.5 m everolimus (lenvatinib plus everolimus vs. everolimus) NOTE: Source: Affinitor USPI; Inlyta USPI; Opdivo USPI; Lenvima USPI. Abbreviation: m, months.

dose reductions seen in the clinical trial to better inform Disclaimer practitioners. The Deputy Editor handling the peer review and decision-making process for Exploratory PRO data demonstrated a numerically worse this article has no relevant employment associations to disclose. FKSI-19 treatment side effect (TSE) subscale score in the cabozantinib arm. The TSE finding is challenging to interpret Authors' Contributions given that the TSE consists of only three questions (diarrhea, Conception and design: H. Singh, M. Brave, J.A. Beaver, C. Liu, G. Kim, nausea, and side-effect bother), and important symptomatic AEs R. Pazdur Development of methodology: H. Singh, M. Brave, J.A. Beaver, Y. Wang, of both cabozantinib and everolimus are not incorporated into R. Sridhara, R. Pazdur the TSE score. The largest effect seen in the PRO results was Acquisition of data (provided animals, acquired and managed patients, increased diarrhea in the cabozantinib arm, consistent with the provided facilities, etc.): R. Pazdur submitted safety data. In summary, cabozantinib demonstrated Analysis and interpretation of data (e.g., statistical analysis, biostatistics, efficacy superior to everolimus, with a statistically significant computational analysis): M. Brave, J.A. Beaver, J. Cheng, S. Tang, E. Zahalka, improvement in PFS, OS, and ORR. The improvements in esti- P. Song, Q. Liu, J. Yu, Y. Wang, P.G. Kluetz, S.R. Daniels, R. Sridhara, A. Ibrahim, G. Kim, R. Pazdur mated median PFS and OS are considered clinically meaningful. Writing, review, and/or revision of the manuscript: H. Singh, M. Brave, The safety profile of cabozantinib at 60 mg daily appears accept- J.A. Beaver, S. Tang, E. Zahalka, T.R. Palmby, P. Song, Q. Liu, C. Liu, J. Yu, able. Therefore, based on a favorable benefit–risk profile and X.H. Chen, X. Wang, Y. Wang, P.G. Kluetz, S.R. Daniels, E.J. Papadopoulos, substantial evidence of safety and efficacy, cabozantinib was R. Sridhara, A.E. McKee, A. Ibrahim, G. Kim, R. Pazdur granted regular approval for the treatment of adult patients with Administrative, technical, or material support (i.e., reporting or organizing advanced RCC who have received prior antiangiogenic therapy. data, constructing databases): M. Brave, J.A. Beaver, R. Venugopal, G. Kim Study supervision: M. Brave, R. Pazdur

Disclosure of Potential Conﬂicts of Interest Received July 12, 2016; revised August 29, 2016; accepted August 31, 2016; No potential conﬂicts of interest were disclosed. published OnlineFirst October 28, 2016.

References 1. National Cancer Institute. SEER Cancer Statistics Factsheets: Kidney and 5. U.S. Food and Drug Administration. Highlights of prescribing information Renal Pelvis Cancer. Bethesda (MD): National Cancer Institute; [cited 2016 (LENVIMA). Silver Spring (MD): U.S. Food and Drug Administration; Jun 27]. Available from: http://seer.cancer.gov/statfacts/html/kidrp.html. 2016 [cited 2016 Jun 27]. Available from: http://www.accessdata.fda. 2. U.S Food and Drug Administration. Highlights of prescribing information gov/drugsatfda_docs/label/2016/206947s003lbl.pdf. (AFINITOR). Silver Spring (MD): U.S. Food and Drug Administration; 6. U.S. Food and Drug Administration. Guidance for industry expedited 2016 [cited 2016 Jun 27]. Available from: http://www.accessdata.fda.gov/ programs for serious conditions – drugs and biologics. Silver Spring (MD): drugsatfda_docs/label/2016/022334s038lbl.pdf. U.S. Food and Drug Administration; 2014 [cited 2016 Jun 27]. Available 3. U.S Food and Drug Administration. Highlights of prescribing information from: http://www.fda.gov/downloads/drugs/guidancecomplianceregula- (INLYTA). Silver Spring (MD): U.S. Food and Drug Administration; toryinformation/guidances/ucm358301.pdf. 2012 [cited 2016 Jun 27]. Available from: http://www.accessdata.fda. 7. Katayama R, Kobayashi Y, Friboulet L, Lockerman EL, Koike S, Shaw AT, gov/drugsatfda_docs/label/2012/202324lbl.pdf. et al. Cabozantinib overcomes crizotinib resistance in ROS1 fusion-pos- 4. U.S Food and Drug Administration. Highlights of prescribing information itive cancer. Clin Cancer Res 2015;21:166–74. (OPDIVO). Silver Spring (MD): U.S. Food and Drug Administration; 8. Zhou L, Liu X-D, Sun M, Zhang X, German P, Bai S, et al. Targeting MET and 2015 [cited 2016 Jun 27]. Available from: http://www.accessdata.fda. AXL overcomes resistance to sunitinib therapy in renal cell carcinoma. gov/drugsatfda_docs/label/2015/125554s012lbl.pdf. Oncogene 2016;35:2687–97.

334 Clin Cancer Res; 23(2) January 15, 2017 Clinical Cancer Research

FDA Approval Summary for Cabozantinib for RCC

9. U.S. Food and Drug Administration. Clinical pharmacology and bio- (METEOR): ﬁnal results from a randomised, open-label, phase 3 trial. metrics review(s). Silver Spring (MD) : U.S. Food and Drug Administration; Lancet Oncol 2016;17:917–27. 2012 [cited 2016 Jun 27]. Available from: http://www.accessdata.fda.gov/ 12. U.S. Food and Drug Administration. Guidance for industry post- drugsatfda_docs/nda/2012/203756Orig1s000PharmR.pdf. marketing studies and clinical trials – implementation of Section 10. Choueiri TK, Escudier B, Powles T, Mainwaring PN, Rini BI, Donskov F, 505 (o)(3) of the Federal Food, Drug, and Cosmetic Act. Silver et al. Cabozantinib versus everolimus in advanced renal-cell carcinoma. Spring (MD): U.S. Food and Drug Administration; 2011 [cited N Engl J Med 2015;373:1814–23. 2016 Jun 27]. Available from: http://www.fda.gov/downloads/ 11. Chouieri TK, Escudier B, Powles T, Tanner NM, Mainwaring PN, Rini BI, drugs/guidancecomplianceregulatoryinformation/guidances/ucm172001. et al. Cabozantinib versus everolimus in advanced renal cell carcinoma pdf.

www.aacrjournals.org Clin Cancer Res; 23(2) January 15, 2017 335

U.S. Food and Drug Administration Approval: Cabozantinib for the Treatment of Advanced Renal Cell Carcinoma

Harpreet Singh, Michael Brave, Julia A. Beaver, et al.

Clin Cancer Res 2017;23:330-335. Published OnlineFirst October 28, 2016.

Updated version Access the most recent version of this article at: doi:10.1158/1078-0432.CCR-16-1073

Cited articles This article cites 4 articles, 1 of which you can access for free at: http://clincancerres.aacrjournals.org/content/23/2/330.full#ref-list-1

Citing articles This article has been cited by 4 HighWire-hosted articles. Access the articles at: http://clincancerres.aacrjournals.org/content/23/2/330.full#related-urls

E-mail alerts Sign up to receive free email-alerts related to this article or journal.

Reprints and To order reprints of this article or to subscribe to the journal, contact the AACR Publications Department at Subscriptions [email protected].

Permissions To request permission to re-use all or part of this article, use this link http://clincancerres.aacrjournals.org/content/23/2/330. Click on "Request Permissions" which will take you to the Copyright Clearance Center's (CCC) Rightslink site.